(Philadelphia, PA) - The cause of
schizophrenia remains a mystery,
despite the millions of dollars
spent trying to discover which genes
play a role in its etiology. In at
least 10 populations around the
world, a significant association
between schizophrenia and the gene
for dysbindin has been noted -
making dysbindin the most highly
replicated schizophrenia-associated
gene described to date. Now,
researchers at the
University of Pennsylvania School of
Medicine are starting to
place where dysbindin fits in the
pathway that leads from a gene to a
psychiatric disorder. Schizophrenia
affects between 1 to 2 percent of
people worldwide during their
lifetime and about 2.2 million
American adults have schizophrenia
in a given year.

Using
quantitative immunohistochemistry in
postmortem brain tissue, the Penn
investigators found that the
expression of dysbindin protein was
reduced in more than 80 percent of
the patients with schizophrenia by
an average of 40 percent relative to
matched healthy controls. (For a
color image illustrating this
comparison, go to:
www.uphs.upenn.edu/news/news_photos/2004/may/arnoldDysbindinColor.html)
“This is among the most significant
findings I’ve seen yet in
schizophrenia postmortem research,
and it represents a critical lead
for understanding schizophrenia,”
says senior author Steven
Arnold, MD, Associate
Professor of Psychiatry and
Neurology. The research appears in
the May issue of the Journal of
Clinical Investigation.

The
scientists also found that, in the
same brain regions in which there
was a decrease in there
was also an increase in the amounts
of presynaptic glutamate packets, or
vesicles, and that these findings
were highly correlated. Synaptic
vesicles form at the ends of nerve
cells and contain chemical
neurotransmitters such as glutamate.
Neurons communicate with each other
by releasing neurotransmitters from
these vesicles. The researchers
surmise that dysbindin affects the
manufacture or breakdown of these
vesicles and, consequently,
glutamate may not be released
properly - thus impairing
communication between neurons.

The
abnormality was most prominent in
the dentate gyrus portion of the
hippocampus. This area of the brain
is especially important for memory,
which is known to be impaired in
schizophrenia. The study’s findings
were independently replicated, using
two collections of postmortem brain
tissue, one maintained by Penn and
another by the Stanley Medical
Research Institute.

“The
next step is to understand what
dysbindin does in the brain,”
explains Arnold. “We’ve found that
dysbindin abnormalities are part of
schizophrenia, but we need to know
much more to translate this
information into practical knowledge
to help patients. In other words, we
need to know what other proteins
dysbindin interacts with and whether
it involves just glutamate or other
neurotransmitters like serotonin,
dopamine or GABA and how dysbindin
affects the electrical activity of
the brain. And, are there medicines
that alter dysbindin expression in
the brain?” To answer these and
other important questions, Arnold
and colleagues are currently
collaborating with other researchers
at the University of Oxford in the
United Kingdom.

“One of
the most exciting parts of this
story is that the extensive work
that has gone on in the genetics of
schizophrenia is finally starting to
bear fruit in terms of identifying
specific genes that we can then
follow-up in the brain,” says
Arnold. “Who would have predicted
that a protein that was first
discovered a few years ago by
muscular dystrophy researchers could
have anything to do with
schizophrenia? The genetics studies
pinpointed a link between dysbindin
and schizophrenia. This clue
prompted us to investigate dysbindin
in the brain where we found that it
is highly expressed and highly
abnormal in schizophrenia.”

Other
Penn researchers collaborating on
this work are Konrad Talbot, Wess L.
Eidem, Edward W. Thompson, Rachel J.
Smith, Chang-Gyu Hahn, John Q.
Trojanowski, and Raquel E. Gur, as
well as Caroline L. Tinsley and
Matthew A. Benson from Oxford
University. The research was
supported in part by the National
Institute of Mental Health.